The All of Us Evenings with Genetics (EwG) Research Program at Baylor College of Medicine (BCM), funded to engage research scholars to work with the All of Us data, developed a training curriculum for the Researcher Workbench, the platform to access and analyze All of Us data. All of Us EwG developed the curriculum so that it could teach scholars regardless of their skills and background in programming languages and cloud computing. All of Us EwG delivered this curriculum at the first annual All of Us EwG Faculty Summit in May 2022. The curriculum was evaluated both during and after the Faculty Summit so that it could be improved for future training.
4'-Carboxyphthalato(1,2-diaminocyclohexane)platinum(II) is a new, second generation platinum analog which had demonstrated in vitro activity in L1210 cell lines resistant to cisplatin and had less nephrotoxicity than did cisplatin in preclinical animal testing. A Phase I trial with this agent has been performed in 45 patients with advanced refractory cancers. Nine dosage levels, ranging from 40 to 800 mg/sq m, were studied. Major toxicities seen were myelosuppression, nephrotoxicity (which was generally mild), nausea and vomiting (which was quantitatively less than that seen with cis-platin), allergic reactions, and a peripheral neuropathy. The dose-limiting toxicity was thrombocytopenia. Pharmacokinetics performed at three dosage levels indicates that 4'-carboxyphthalato-(1,2-diaminocyclohexane)platinum(II) has a long t1/2 of 20 to 30 hr (total platinum) and is only partially excreted in the urine and that a high proportion of the drug is nonfilterable within 30 to 60 min of administration. Therapeutic responses were seen in nasopharyngeal carcinoma, adenocarcinoma of the cervix, and lung and gastric cancer. As a starting dose for Phase II studies, which are planned for patients with ovarian, testicular, lung, gastric, and esophageal cancers, 640 mg/sq m given every 3 to 4 weeks is recommended.
<div>Abstract<p>Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. <i>PIK3CA</i> is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short-course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed <i>ex vivo</i> expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of precancerous breast lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer.</p>Prevention Relevance:<p>PI3K protein is abnormally high in breast precancerous lesions. This preclinical study demonstrates that the FDA-approved anti-PI3K inhibitor alpelisib can prevent breast cancer and thus warrant future clinical trials in high-risk women.</p></div>
<div>Abstract<p>Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. <i>PIK3CA</i> is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short-course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed <i>ex vivo</i> expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of precancerous breast lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer.</p>Prevention Relevance:<p>PI3K protein is abnormally high in breast precancerous lesions. This preclinical study demonstrates that the FDA-approved anti-PI3K inhibitor alpelisib can prevent breast cancer and thus warrant future clinical trials in high-risk women.</p></div>
Targeting HER2 is one of the greatest successes in oncology, and has resulted in the generation of a wide array of HER2-targeting agents. Our genomic approaches are revealing other mechanisms of HER2 activation, such as our discovery of activating HER2 mutations in different cancer types. From initial breast cancer and SUMMIT trial data, the pan-HER drug neratinib as monotherapy showed initial clinical response in ER+ breast cancer, but with frequent early relapse. This study investigates the preclinical efficacy of anti HER2 agents alone or in combination with endocrine therapy agents or in combination with CDK4/6 inhibitors using ER+/HER2 mutant cell lines and ex vivo HER2 mutant patient derived xenograft (PDX) model. ER+ breast cancer cell lines (T47D and MCF7) stably expressing HER2V777L, and ER+/HER2 mutant PDX model (HER2G778_P780 dup) were used to examine HER2 signaling. We found that MCF7/T47D cells expressing HER2V777L and HER2G778_P780 dup PDX tumors showed strongly activated autophosphorylation of HER2 and increased expression of CDK4, CDK6, phospho-Rb, and cyclin D1 as compared to MCF7/T47D cells expressing HER2WT or ER+/non-HER2mut PDX model, suggesting that HER2 mutations preferentially depend on CDK4/6 signaling for cell growth. Additionally, we showed that activating MCF7 HER2V777L cause resistance to endocrine therapy treatment (fulvestrant IC50 >5μM). Further, we show that neratinib alone is effective at higher concentrations (IC50 < 2μM) in MCF7/HER2V777L cells. Next we showed that abemaciclib alone exhibited moderate activity against MCF7 HER2V777L cells (IC50 < 0.4μM) and additional activity in combination with neratinib (IC50 < 0.06μM) was seen. Moreover, ex vivo HER2G778_P780 dup cells are relatively resistant to fulvestrant alone (IC50 < 0.2μM), neratinib alone (IC50 < 0.006μM), abemaciclib alone (IC50 < 0.04μM), and neratinib in combination with abemaciclib (IC50 < 0.005μM), suggesting that patients harboring ER+/HER2-mutant tumors may benefit from neratinib in combination with abemaciclib. Therefore, we propose that simultaneous targeting of both HER2 and the CDK4/6 axis is required for maximal inhibition of ER+ breast cancers harboring HER2 activating mutations.Citation Format: Vaishnavi Devarakonda, LaTerrica Williams, Sinem Seker, Jonathan T. Lei, Purba Singh, Airi Han, Meenakshi Anurag, Kimberly R. Holloway, Alana L. Welm, Matthew J. Ellis, Shyam M. Kavuri. Evaluating preclinical efficacy of anti-HER2 drug combinations using ER+/HER2 mutant models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 850.
### O1 IL-15 primes an mTOR-regulated gene-expression program to prolong anti-tumor capacity of human natural killer cells #### Andreas Lundqvist1, Vincent van Hoef1, Xiaonan Zhang1, Erik Wennerberg2, Julie Lorent1, Kristina Witt1, Laia Masvidal Sanz1, Shuo Liang1, Shannon Murray3, Ola Larsson1,
Meeting abstracts T cell immunotherapy with genetically modified T cells expressing chimeric antigen receptors (CARs) has shown promise in preclinical models as well as early clinical studies. However, patients with solid tumors often do not respond as well as patients with hematological
<p>Supplementary Figure S1 show shows biochemical staining on MCF10A-PIK3CAH1047R mammary tumors. Supplementary Figure S2 shows expression of ERα in MCF10A-PIK3CAH1047R mammary tumors. Supplementary Figure S3 shows response of MCF10A-PIK3CAH1047R cells to fulvestrant in vitro and in vivo. Supplementary Figure S4 shows droplet digital PCR (ddPCR) analysis. Supplementary Figure S5 shows tolerance of alpelisib administration in mice. Supplementary Figure S6 shows short term alpelisib does not affect lung or bone metastasis from MCF10A-PIK3CAH1047R mammary tumors.</p>
Abstract Objective Educational offerings to fill the bioinformatics knowledge gap are a key component to enhancing access and use of health data from the All of Us Research Program. We developed a Train the Trainer-based, innovative training series including project-based learning, modular on-demand demonstrations, and unstructured tutorial time as a model for educational engagement in the All of Us community. Materials and Methods We highlight our training modules and content, with training survey data informing cycles of development in the creation of a 6-module training series with modular demonstrations. Results We have conducted 2 public iterations of the Train the Trainer (Tx3) Series based on survey feedback while training over 300 registered researchers to access and analyze data on the All of Us Researcher Workbench. Discussion and Conclusion Future directions of the Tx3 Series include enhanced focus on project-based learning and learner requests for modularity and asynchronous materials access.
<p>Supplementary Figure S1 show shows biochemical staining on MCF10A-PIK3CAH1047R mammary tumors. Supplementary Figure S2 shows expression of ERα in MCF10A-PIK3CAH1047R mammary tumors. Supplementary Figure S3 shows response of MCF10A-PIK3CAH1047R cells to fulvestrant in vitro and in vivo. Supplementary Figure S4 shows droplet digital PCR (ddPCR) analysis. Supplementary Figure S5 shows tolerance of alpelisib administration in mice. Supplementary Figure S6 shows short term alpelisib does not affect lung or bone metastasis from MCF10A-PIK3CAH1047R mammary tumors.</p>
